Apoptotic exosome-like vesicles regulate endothelial gene expression, inflammatory signaling, and function through the NF-κB signaling pathway.
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ABSTRACT:
PROVIDER: PRJNA594542 | ENA |
REPOSITORIES: ENA
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Project description:Persistent endothelial injury promotes maladaptive responses by favoring the release of factors leading to perturbation in vascular homeostasis and tissue architecture. Caspase-3 dependent death of microvascular endothelial cells leads to the release of unique apoptotic exosome-like vesicles (ApoExo). Here, we evaluate the impact of ApoExo on endothelial gene expression and function in the context of a pro-apoptotic stimulus. Endothelial cells exposed to ApoExo differentially express genes involved in cell death, inflammation, differentiation, and cell movement. Endothelial cells exposed to ApoExo showed inhibition of apoptosis, improved wound closure along with reduced angiogenic activity and reduced expression of endothelial markers consistent with the first phase of endothelial-to-mesenchymal transition (endoMT). ApoExo interaction with endothelial cells also led to NF-κB activation. NF-κB is known to participate in endothelial dysfunction in numerous diseases. Silencing NF-κB reversed the anti-apoptotic effect and the pro-migratory state and prevented angiostatic properties and CD31 downregulation in endothelial cells exposed to ApoExo. This study identifies vascular injury-derived extracellular vesicles (ApoExo) as novel drivers of NF-κB activation in endothelial cells and demonstrates the pivotal role of this signaling pathway in coordinating ApoExo-induced functional changes in endothelial cells. Hence, targeting ApoExo-mediated NF-κB activation in endothelial cells opens new avenues to prevent endothelial dysfunction.
2019-12-11 | GSE141731 | GEO
Project description:Constitutive activation of the anti-apoptotic NF-κB signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) that is characterized by adverse survival. Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 mutants in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-Catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-Catenin destruction complex was independent of CARMA1-BCL10-MALT1 (CBM) complex formation or constitutive NF-κB activation and promoted the stabilization of β-Catenin. Elevated β-Catenin expression was detected in cell lines and biopsies from ABC DLBCL that rely on chronic BCR signaling. Increased β-Catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-Catenin enhanced expression of immune suppressive IL-10 and repressed anti-tumoral CCL3, indicating that β-Catenin may induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-Catenin signaling by gain-of-function mutations in CARMA1 can augment WNT stimulation and is required for maintaining high expression of distinct NF-κB target genes and can thereby trigger cell intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.
2016-01-01 | GSE70025 | GEO
Project description: Not available
| S-EPMC7387353 | biostudies-literature
Project description:Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T-cells into regulatory T-cells in vitro. The marker CD69 is a target of canonical NF-κB signaling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3+ T-cells were activated and cultured in the presence or absence of MSCs. CD4+ cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 and a siRNA against RELB were used to explore the differential roles of canonical and non-canonical NF-κB signaling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69+ cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69+ cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signaling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signaling on the 3rd day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signaling. In order to study the molecular basis by which Multipotent Mesenchymal Stromal/Stem Cells (MSC) exert their immune regulatory function, immunomagnetically purified CD3+ T-cells from the peripheral blood of 3 individuals were activated and cultured in the presence or absence of MSCs. Following 5 days, CD4+ and CD8+ T-cells were further immunomagnetically selected and their gene expression profiles were obtained by microarrays and compared. Paired samples from 3 individuals were used for this analysis.
2011-08-02 | E-GEOD-31153 | biostudies-arrayexpress
Project description:Background: The most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC), has a worse prognosis and a higher probability of relapse since there is a narrow range of treatment options. Identifying and testing potential therapeutic targets for the treatment of TNBC is of high priority. Methods: Using a transcriptional signature of triple-negative breast cancer collected from Gene Expression Omnibus (GEO), CMap was utilized to reposition compounds for the treatment of TNBC. CCK8 and colony formation experiments were performed to detect the effect of the candidate drug on the proliferation of TNBC cells, while flow cytometry was used to detect cell apoptosis. Meanwhile, transwell assay was implemented to detect cell metastasis change caused by the candidate drug. Moreover, the proteomic approach was presently ongoing to evaluate the underlying mechanism of the candidate drug in TNBC. Furthermore, drug affinity responsive target stability (DARTS) coupled with LC-MS/MS was carried out to explore the potential drug target candidate in TNBC cells. Results: We found that the most widely used medication, eugenol, reduced the growth and metastasis of TNBC cells. According to the underlying mechanism revealed by proteomics, eugenol could inhibit TNBC cell proliferation via the NOD1-NF-κB signaling pathway. DARTS experiment further revealed that eugenol may bind to NF-κB in TNBC cells. Concludes: Our findings pointed out that eugenol was a potential candidate drug for the treatment of TNBC.
2023-05-10 | PXD039305 | Pride
Project description:MTD project_description Inflammation and decreased stem cell function characterize organism aging, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signals, by increasing chromatin accessibility of inter-/intra-genic and enhancer regions. Rad21/NF-κB are required for normal differentiation, but limit self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB dependent manner. HSCs from aged mice fail to downregulate Rad21/cohesin and inflammation/differentiation inducing signals in the resolution phase after acute inflammation. and The inhibition of cohesin/NF-κB is sufficient to revert the hypersensitivity of aged HSPCs to inflammation-induced differentiation. During aging, myeloid-biased HSCs with disrupted and naturally occurring reduced expression of Rad21/cohesin are increasingly selected over lymphoid-biased HSCs. Together, Rad21/cohesin mediated NF-κB signaling limits HSPC function during aging and selects for cohesin deficient HSCs with myeloid skewed differentiation.
2018-11-28 | PXD011537 | Pride
Project description:T cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that the majority of TALL patients carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively-active Notch1 activates the NF-κB pathway transcriptionally and via the IκB kinase (IKK) complex, thereby causing increased expression of multiple well-characterized NF-κB target genes in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-κB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These studies identify NF-κB as one of the major mediators of NOTCH1-induced transformation and suggest that the NF-κB pathway is a potential target of future targeted therapies of T-ALL. Keywords: gene expression analysis, signaling pathway alteration
2006-12-02 | GSE6396 | GEO
Project description:Activation of NF-κB-signalling is key in the pathogenesis of chronic kidney diseases (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair and hence maintain a healthy kidney. To investigate the relationship between activated and inactivated NF-κB signaling on the pathogenesis of CKD, mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine) were used. Blood pressure, serum creatinine and urinary albumin-to-creatinine-ratio markedly increased in NF-κB activated and inactivated mice compared to controls. PAS-, Masson trichrome-, and Sirius-Red-staining, as well as α-SMA immunofluorescence staining in kidneys of NF-κBC59A, and NF-κBC59S mice demonstrated kidney fibrosis in both models. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared to wild-type mice. KEGG enrichment analysis of RNA sequencing data revealed that the PPAR pathway was most markedly upregulated in both mouse models. However, there were also differences such as fatty acid degradation, peroxisome and glutathione metabolism, and downregulation of retinol metabolism in NF-κBC59A mice with decreased NF-κB signaling, whereas cell adhesion molecules, fat digestion, and absorption were upregulated in mice with activated NF-κB signaling (NF-κBC59S mice). In conclusion, using mice models with primarily activated and partially inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between kidney function as well as morphology and the activation of the NF-κB pathway.
2023-09-30 | GSE244099 | GEO
Project description:A20 is known key regulator of NF-κB activity and inflammatory response, but its role in the control of cell death receptor signaling is not completely understood. Although A20 is widely accepted anti-apoptotic protein, we demonstrate that elevated expression of A20 in both, human and murine keratinocytes results in sensitisation to TNF-induced cell death. We prove that the Ripoptosome formation in A20 overexpressing cells is prerequisite for the TNF-induced cell death execution. We demonstrate that both canonical and non-canonical NF-κB signaling pathways are regulated upon increase of A20 expression. A20 dependent alteration of cIAPs and TRAF1 expressions are involved in the multiple level control of cell death in keratinocytes with elevated A20 expression.
2020-02-20 | GSE128248 | GEO
Project description:A20 is known key regulator of NF-κB activity and inflammatory response, but its role in the control of cell death receptor signaling is not completely understood. Although A20 is widely accepted anti-apoptotic protein, we demonstrate that elevated expression of A20 in both, human and murine keratinocytes results in sensitisation to TNF-induced cell death. We prove that the Ripoptosome formation in A20 overexpressing cells is prerequisite for the TNF-induced cell death execution. We demonstrate that both canonical and non-canonical NF-κB signaling pathways are regulated upon increase of A20 expression. A20 dependent alteration of cIAPs and TRAF1 expressions are involved in the multiple level control of cell death in keratinocytes with elevated A20 expression.
2020-02-20 | GSE128247 | GEO